The primary goal of this research is to develop a strategy for on-line control of protein glycosylation during monoclonal antibody production. The PIs will develop and validate experimentally, a novel multi-loop, on-line control system incorporating a multi-scale model integrated with a comprehensive multi-rate measurement system. The specific question to be answered is: When manufacturing monoclonal antibodies (MAb) using Chinese Hamster Ovary (CHO) cells, how does one achieve effective on-line control of protein glycosylation and hence assure acceptable MAb bioactivity in vivo?
The specific tasks that will be performed are:
Task 1: Inner-loop Control System Development: develop and implement a multivariable inner-loop control system to maintain bioreactor conditions consistently at desired set-points. Task 2: Advanced Bioprocess Development and Optimization: develop a stable MAb-producing CHO K1 cell line; develop glycosylation assays for quantifying both macro- and micro-heterogeneity; and determine the optimal conditions for robust attainment of quality i.e., desired glycosylation pattern and activity. Task 3: Outer-loop Control System Development; Overall System Integration/Implementation: develop an outer-loop control scheme which employs glycosylation measurements and state estimates of glycosylation, integrate this with the inner loop, and implement the complete multi-loop control scheme to demonstrate effective on-line control of glycosylation.
Monoclonal antibodies (MAbs), proteins that exhibit high specificity for a target antigen, are used therapeutically in oncology, organ transplantation, inflammatory disease, etc. With more than 200 in development pipelines, MAbs have become the fastest growing sector of the biopharmaceutical industry. As with other manufactured products, MAbs are therapeutically effective only when their product quality attributes (bioactivity, potency, purity, etc.) lie within a specific range of values. However, meeting these often stringent quality criteria requirements is currently a major challenge for manufacturers because the MAb manufacturing process is very complex and not well-characterized. In addition, with current technology, the majority of quality control assays must be performed off-line and post-production. Nevertheless, the necessity to guarantee the safety and effectiveness of all pharmaceutical products has prompted the FDA to recommend strongly that manufacturers demonstrate the ability to ensure product quality online during production. To date, no such technique for online quality control in MAb manufacturing exists.
Intellectual Merit This research will demonstrate experimentally, on-line control of glycosylation, and establish general principles for achieving such a challenging objective in practice. The PIs envision two kinds of primary impact for this research: (i) Technical: the development of many pioneering techniques central to the overall success of the research, specifically: multi-scale modeling and control of molecular processes in the cell; and the design/ implementation of multi-rate, multi-loop control systems for non-linear semi-batch bioprocesses. (ii) Implementational: a demonstration of how to integrate various categories of measurement systems (probes, analyzers, and assays) with control systems via OPC software?the emerging industry standard for universal connectivity between process equipment and control systems.
Broader Impact The outcomes of this research will have a direct impact on industrial practice. First, industry leaders in bioprocess monitoring and control systems hardware are involved, and will transmit the results to their customers. Second, the strategy developed for on-line control of glycosylation can be applied to other quality attributes in any therapeutic protein product. Thus, if successful, this work could potentially revolutionize how quality control is achieved in the biopharmaceutical industry. Third, in providing initial funding for generating preliminary results, the FDA plans to train inspectors on the University of Delaware experimental system. Fourth, the research results will be incorporated into the process dynamics and control course, and widely disseminated through publications and presentations to educators and researchers. Finally, the PI, as a minority himself, is committed to recruiting under-represented groups into the chemical engineering discipline in general and should be able to attract minority students to participate in this effort. The graduate student currently working on the project, who generated the preliminary results, is female.
